Telomerase deficiency in bone marrow-derived cells attenuates angiotensin II-induced abdominal aortic aneurysm formation.
Telomerase deficiency in bone marrow-derived cells attenuates angiotensin II-induced abdominal aortic aneurysm formation.
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DOI：
10.1161/atvbaha.110.218545
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发表时间：
2011-02
期刊：
影响因子：
--
通讯作者：
Bruemmer D
中科院分区：
文献类型：
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作者：
Findeisen HM;Gizard F;Zhao Y;Cohn D;Heywood EB;Jones KL;Lovett DH;Howatt DA;Daugherty A;Bruemmer D
Abdominal aortic aneurysms (AAA) are an age-related vascular disease and an important cause of morbidity and mortality. In this study, we sought to determine whether the catalytic component of telomerase, telomerase reverse transcriptase (TERT), modulates angiotensin (Ang) II-induced AAA formation. LDL receptor-deficient (LDLr−/−) mice were lethally irradiated and reconstituted with bone marrow-derived cells from TERT-deficient (TERT−/−) mice or littermate wild-type mice. Mice were placed on a diet enriched in cholesterol, and AAA formation was quantified after 4 weeks of Ang II infusion. Repopulation of LDLr−/− mice with TERT−/− bone marrow-derived cells attenuated Ang II-induced AAA formation. TERT-deficient recipient mice revealed modest telomere attrition in circulating leukocytes at study endpoint without any overt effect of the donor genotype on white blood cell counts. In mice repopulated with TERT−/− bone marrow aortic matrix metalloproteinase-2 (MMP-2) activity was reduced, and TERT−/− macrophages exhibited decreased expression and activity of MMP-2 in response to stimulation with Ang II. Finally, we demonstrate in transient transfection studies that TERT overexpression activates the MMP-2 promoter in macrophages. TERT-deficiency in bone marrow-derived macrophages attenuates Ang II-induced AAA formation in LDLr−/− mice and decreases MMP-2 expression. These results point to a previously unrecognized role of TERT in the pathogenesis of AAA.
